Genetic relations between leukocyte counts, type 1 diabetes, and coronary artery disease

Hypothesis/AimType 1 diabetes (T1D) is associated with excess coronary artery disease (CAD) risk even when known cardiovascular risk factors are accounted for. Genetic perturbation of hematopoiesis that alters leukocyte production is a novel independent modifier of CAD risk. We examined whether there are shared genetic determinants and causal relationships between leukocyte counts, T1D, and CAD. MethodsGenome-wide association studies (GWAS) summary statistics were utilized to perform pairwise linkage disequilibrium score regression (LDSC) and heritability estimation from summary statistics ({rho}-HESS) to respectively estimate the genome-wide and local genetic correlations, and two-sample Mendelian randomization (MR) to estimate the causal relationships between leukocyte counts (335 855 healthy subjects), T1D (18 942 cases, 501 638 controls), and CAD (122 733 cases, 424 528 controls). ResultsThere was significant genome-wide genetic correlation (rg) between T1D and CAD (rg = 0.088; P = 9.0e-03) and both diseases shared significant genome-wide genetic determinants with eosinophil count (rg(T1D) = 0.093, P = 7.20e-03; rg(CAD) = 0.092, P = 3.68e-06) and lymphocyte count (rg(T1D) = -0.052, P = 2.80e-02; rg(CAD) = 0.1761, P = 1.82e-15). Sixteen independent loci showed stringent Bonferroni significant local genetic correlations between leukocyte counts, T1D and/or CAD. Cis-genetic regulation of the expression levels of genes within loci that are shared between T1D and CAD were associated with both diseases as well as leukocyte counts, including SH2B3, CTSH, MORF4L1, CTRB1, CTRB2, CFDP1, and IFIH1. Genetically predicted lymphocyte, neutrophil, and eosinophil counts were associated with T1D and CAD (lymphocyte odds ratio (OR)T1D = 0.667, P = 2.02e-19; ORCAD =1.085, P = 2.67e-06; neutrophil ORT1D = 0.82, P = 5.63e-05; ORCAD = 1.17, P = 5.02e-14; and eosinophil ORT1D: 1.67, P = 4.45e-25; ORCAD: 1.07; P = 2.02e-03). Conclusions/InterpretationsThis study sheds light on shared genetic mechanisms that underlie T1D and CAD, which may contribute to their co-occurrence through regulation of gene expression and leukocyte counts. This study also identifies molecular targets for further investigation for disease prediction and potential drug discovery. Research in ContextO_ST_ABSWhat is already known about the subject?C_ST_ABSO_LIGenetic factors have been shown to contribute to the occurrence of coronary artery disease (CAD) in type 1 diabetes (T1D), but the mechanisms are unknown. C_LIO_LIGenetic perturbation of hematopoiesis that alters leukocyte production is associated with CAD risk and clinical observations have documented altered leukocyte counts in T1D. However, it is unknown whether altered leukocyte frequencies contribute to T1D and the co-occurrence of T1D and CAD or these reflect reverse causation. C_LI What is the key question?O_LIDo T1D and CAD share genetic determinants with leukocyte counts, and if so, are genetically predicted leukocyte counts associated with risk of T1D or CAD and their co-occurrence? C_LI What are the new findings?O_LIT1D and CAD share significant genetic architecture, and both diseases share significant genetic determinants with eosinophil and lymphocyte counts. C_LIO_LIGenetically predicted eosinophil, lymphocyte, and neutrophil counts are associated with risk of T1D and CAD. C_LIO_LIGenetic regulation of the expression levels of genes in shared loci between T1D and CAD are associated with both diseases and leukocyte counts. C_LI How might this impact on clinical practice in the foreseeable future?O_LIGenetic heritability for T1D is shared with CAD risk and leukocyte counts, and the counts of eosinophils, lymphocytes, and neutrophils are associated with both diseases. C_LI